Phenyl Chlorothionocarbonate

[1005-56-7]  · C7H5ClOS  · Phenyl Chlorothionocarbonate  · (MW 172.64)

(forms thionocarbonate ester derivatives of alcohols which can be deoxygenated with tin hydride reagents;1-5 converts ribonucleosides to 2-deoxynucleosides;2 provides allylic thionocarbonates which undergo [3,3]-sigmatropic shifts;6-9 provides precursors for radical bond-forming reactions;10,11 reagent for thioacylation12-16)

Physical Data: bp 81-83 °C/6 mmHg; fp 81 °C; d 1.248 g cm-3.

Solubility: sol chloroform, THF.

Form Supplied in: colorless liquid.

Handling, Storage, and Precautions: corrosive; moisture sensitive; should be stored in airtight containers which exclude moisture; incompatible with alcohol solvents.

Deoxygenation of Secondary Alcohols.

Reaction of secondary alcohols with the reagent in the presence of Pyridine or 4-Dimethylaminopyridine (DMAP) provides thiocarbonate ester derivatives which can be reduced to alkanes using Tri-n-butylstannane (eq 1).1 The advantage of this method is the ability to deoxygenate alcohols via radical intermediates and thereby avoid problems associated with ionic reaction conditions (i.e. carbonium ion rearrangements, reduction of other functional groups). This method is particularly useful for the conversion of ribonucleosides to 2-deoxynucleosides. For example, adenosine can be converted to 2-deoxyadenosine in 78% overall yield by initial protection of the 3- and 5-hydroxyl groups as a cyclic disiloxane, thiocarbonylation, reductive cleavage, and then final deprotection using a fluoride source (eq 2).2 Treatment of 2-bromo-3-phenoxythiocarbonyl nucleosides with tributyltin hydride affords 2,3-didehydro-2,3-dideoxy nucleosides via radical b-elimination.3

Synthetic intermediates can be selectively deoxygenated without reduction of other functional groups such as esters, ketones, and oxime ethers (eq 3),4 as well as epoxides, acetate esters, and alkenes.5

Sigmatropic Rearrangements of Allylic Thionocarbonates.

The reaction of allyl alcohols with aryl chlorothionocarbonates affords S-allyl aryl thiocarbonates by [3,3]-sigmatropic rearrangement via the intermediate thionocarbonate esters.6-9 For example, treatment of 2-methyl-1-penten-3-ol with the reagent in pyridine at -20 °C affords phenyl 2-methyl-2-pentenyl thionocarbonate in 67% yield (E:Z = 96.5:3.5).7 This type of rearrangement, coupled with tin hydride mediated reduction of the phenyl thiocarbonate ester product, was used as a key step in the synthesis of isocarbacyclin (eq 4).8 Rearrangement of cyclic thionocarbonates contained in eight-membered rings or smaller provides two-atom ring enlarged thiocarbonates having (Z) double bond geometry (eq 5).9 Depending on the system, the cyclic thiocarbonates are obtained by either treatment of the diol monothionocarbonate with base or by reaction of the diol with 1,1-thiocarbonyldi-2,2-pyridone. Cyclic thionocarbonates of ring size nine or larger afford ring expanded products with exclusive (E) double bond geometry in modest yields.

Radical Coupling and Cyclization Reactions.

Phenyl thionocarbonate esters derived from alcohols serve as efficient precursors for the generation of radical intermediates which can be used for the formation of new carbon-carbon bonds. For example, a 4-thionocarbonate ester derived from L-lyxose undergoes a stereoselective allylation upon photolysis in toluene in the presence of 2.0 equiv of Allyltributylstannane (eq 6).10 Photochemical initiation is preferable to chemical initiation using Azobisisobutyronitrile which results in the formation of side products at the expense of the desired product. The allylation product was used further in a total synthesis of pseudomic acid C.

Oxime ethers derived from hydroxy aldehydes, upon conversion to their phenyl thionocarbonate esters, undergo radical cyclizations resulting in the formation of carbocycles.11 For example, an oxime ether obtained from D-glucose is converted into its phenyl thionocarbonate ester at C-5 and, upon heating in benzene in the presence of tributyltin hydride, affords cyclopentanes in 93% yield as a 62:38 mixture of two diastereomers (eq 7). In general, only low to modest stereoselectivity between the newly formed stereocenters is observed in a number of substrates examined.

Thioacylation Reagent.

The regioselective thioacylation of unprotected carbohydrates via the agency of Di-n-butyltin Oxide and the reagent has been investigated.12 Glycopyranosides having a cis-diol arrangement, e.g. galactose, form cyclic thiocarbonates which can be either converted into dihydropyranosides using the Corey elimination procedure or deoxygenated to a mixture of 3- and 4-deoxyglycopyranosides (eq 8). Methyl D-glucopyranoside is monothioacylated with the regioselectivity dependent upon the configuration at the anomeric carbon; the a-epimer gives 83% of 2-thionocarbonate and the b-epimer gives 85% of 6-thionocarbonate. Further treatment with tributyltin hydride affords the corresponding deoxyglucose derivatives in high yield.

In a key step leading to a synthesis of saxitoxin, radical fragmentation of a pyrazolidine ring followed by intramolecular thioacylation afforded the ring expanded tetrahydropyrimidine intermediate (eq 9).13 The thionocarbamate activation of the pyrazolidine N-H was found to be necessary to effect the desired transformation.

The intramolecular thioacylation of an ester enolate was used for the synthesis of 2-alkylthiopenem carboxylic acid derivatives.14 Sequential acylations have led to the synthesis of zwitterionic pyrazole-5-thiones from acyclic precursors,15 whereas 2-ethoxyoxazolidines react with the reagent to afford the products of N-acylation.16

Heating of O-phenyl thionocarbonates of pyrrolidine and piperidine-2-ethanols in acetonitrile gives a ring expanded azepine or an octahydroazocine accompanied by the pyrrolidine and piperidine O-phenyl ethers (eq 10).17 These products arise via the internal expulsion of carbonyl sulfide, leading to formation of an azetidinium intermediate followed by nucleophilic ring opening with phenoxide ion.

Related Reagents.

Carbon Disulfide; RT143-.

1. Barton, D. H. R.; Subramanian, R. JCS(P1) 1977, 1718.
2. Robins, M. J.; Wilson, J. S. JACS 1981, 103, 932; Robins, M. J.; Wilson, J. S.; Hansske, F. JACS 1983, 105, 4059.
3. Serafinowski, P. S 1990, 411.
4. Martin, S. F.; Dappen, M. S.; Dupre, B.; Murphy, C. J. JOC 1987, 52, 3706.
5. Schuda, P. F.; Potlock, S. J.; Wannemacher, R. W., Jr. J. Nat. Prod. 1984, 47, 514.
6. Garmaise, D. L.; Uchiyama, A.; McKay, A. F. JOC 1962, 27, 4509.
7. Faulkner, D. J.; Petersen, M. R. JACS 1973, 95, 553.
8. Torisawa, Y.; Okabe, H.; Ikegami, S. CC 1984, 1602.
9. Harusawa, S.; Osaki, H.; Kurokawa, T.; Fujii, H.; Yoneda, R.; Kurihara, T. CPB 1991, 39, 1659.
10. Keck, G. E.; Kachensky, D. F.; Enholm, E. J. JOC 1985, 50, 4317.
11. Bartlett, P. A.; McLaren, K. L.; Ting, P. C. JACS 1988, 110, 1633.
12. Haque, M. E.; Kikuchi, T.; Kanemitsu, K.; Tsuda, Y. CPB 1987, 35, 1016.
13. Jacobi, P. A.; Martinelli, M. J.; Polanc, S. JACS 1984, 106, 5594.
14. Leanza, W. J.; DiNinno, F.; Muthard, D. A.; Wilkering, R. R.; Wildonger, K. J.; Ratcliffe, R. W.: Christensen, B. G. T 1983, 39, 2505.
15. Grohe, K.; Heitzer, H.; Wendisch, D. LA 1982, 1602.
16. Widera, R.; Muehlstaedt, M. JPR 1982, 324, 1005.
17. Sakanoue, S.; Harusawa, S.; Yamazaki, N.; Yoneda, R.; Kurihara, T. CPB 1990, 38, 2981.

Eric D. Edstrom

Utah State University, Logan, UT, USA

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